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Heating Things Up in a Volatile Marriage…Bispecific Antibody Therapy in Prostate Cancer

They say prostate cancer has a “cold” tumor microenvironment. Prostate cancer generally harbors low mutational complexity,1 resulting in less cytotoxic T cell infiltration into the tumor microenvironment. Hence, the term “hot” vs. “cold” tumor implies how generally inflamed the tumor microenvironment is with immune cells. It certainly would be of interest to the field to develop a therapy that could redirect cytotoxic T cells to the prostate tumor microenvironment to “heat” things up against the tumor and increase antitumor activity. Bispecific antibodies have the potential to accomplish this goal.

Bispecific antibodies are engineered utilizing fragment antigen binding arm exchange from 2 parental antibodies. With this technology, one could target a couple of different tumor antigens or checkpoints simultaneously. Additionally, a bispecific antibody could be engineered to engage a patient’s endogenous T cells and marry that T cell to a choice tumor-specific antigen. This could result in increased cytotoxic T cell infiltration into the tumor microenvironment and direct engagement with tumor cells, resulting in improved tumor cell elimination.

Early phase trials using bispecific antibody therapy have begun in multiple cancers, including prostate cancer. At ASCO 2019, we saw early results of Pasotuxizumab (AMG 212/BAY 2010112), a CD3 and prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) in patients with metastatic castration-resistant prostate cancer (mCRPC).2 PSMA is highly expressed in prostate cancer, making it an attractive target for both imaging and therapeutic targeting. CD3 is expressed on T cells, therefore, Psotuxizumab facilitates the joint binding of a T cell with a prostate cancer cell, forming a cytolytic immune synapse that yields antigen-dependent target cell lysis T-cell activation and cytokine release.3

In this phase 1 trial, presented at ASCO 2019, mCRPC patients refractory to abiraterone and/or enzalutamide and also to at least one taxane-based chemotherapeutic were treated either with daily subcutaneous administration or continuous intravenous infusion in 5 weeks on, 1 week off schedule. Sixteen patients were treated at doses ranging from 5 ug/day to 80 ug/day. The maximum tolerated dose was not reached due to a change in the study sponsor. Three of 16 (19%) patients had a >50% PSA decline, but 14/16 had some level of PSA decline. This measure of antitumor activity was dose-dependent. Two patients had long-term PSA responses, one for 14 and the other for 19.4 months. The latter patient had a soft tissue complete response and evidence of response in bone metastases by PSMA PET/CT. There was some level of cytokine release syndrome identified in 6 of the patients, but only 1 patient had a serious adverse event (fatigue). Hence, this demonstrates promising early clinical activity for a new class of agents in a heavily pre-treated population with mCRPC.

Other similar such agents are entering clinical trials. One bispecific antibody agent, also targeting CD3 and PSMA, is termed a DuoBody®. Another prominent target, highly expressed on prostate cancer cells, is STEAP1.4 Another bispecific antibody will soon enter the clinical trial arena with the goal of marrying CD3 positive T cells to STEAP1 expressing prostate cancer cells.

Although most early trials are utilizing bispecific antibodies to create the volatile marriage of T cells to prostate tumor cells, as described above, other approaches are being broached as well. For example, the concept of checkpoint inhibition with anti-PD-(L)1 therapy is already being regularly utilized in many different cancers. Additionally, inhibition of CTLA-4 in combination therapy trials affords the possibility of additive or synergistic value by inhibiting two unique checkpoints that otherwise would quell cytotoxic T cell activity. A bispecific antibody that inhibits both CTLA-4 and LAG3 would inhibit two unique checkpoints and when combined with an agent like pembrolizumab would enact triple checkpoint blockade. This concept of multi-checkpoint blockade is being studied in the DUET-4 trial in patients with prostate and other malignancies. Although this bispecific antibody is not facilitating the marriage, it is serving to increase the volatility of a previously dull relationship.

Below, I highlight a few such trials, utilizing bispecific antibodies, to facilitate these heated exchanges.

Highlighted trials for prostate cancer patients using bispecific antibodies


Written by: Evan Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine,  Member, Fred Hutchinson Cancer Research Center and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center

References
1. Lawrence MS et al. "Mutational heterogeneity in cancer and the search for new cancer-associated genes." Nature: International Journal of Science. 2013. doi: 10.1038/nature12213.
2. Horst-Dieter H et al. "Phase 1 study of pasotuxizumab (BAY 2010112), a PSMA-targeting Bispecific T cell Engager (BiTE) immunotherapy for metastatic castration-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology. 2019. DOI: 10.1200/JCO.2019.37.15_suppl.5034. 
3. Friedrich M, Raum T, Lutterbuese R, et al. Regression of human prostate cancer xenografts in mice by AMG 212/BAY2010112, a novel PSMA/CD3-Bispecific BiTE antibody cross-reactive with non-human primate antigens. Molecular cancer therapeutics 2012;11:2664-73.
4. Barroca-Ferreira J et al. "Targeting STEAP1 Protein in Human Cancer: Current Trends and Future Challenges." Current Cancer Drug Targets. 2018. doi: 10.2174/1568009617666170427103732.